The prognosis for patients with pancreatic cancer is exceedingly poor. Even with complete surgical resection and adjuvant chemoradiation, only 20% of patients survive five years. Thus, better therapeutic approaches are needed. To this end, the applicant's research group has previously identified CaSm as a potential molecular target for pancreatic cancer. Besides being highly expressed in pancreatic cancer, preliminary work inhibiting CaSm expression in preclinical models of pancreatic cancer successfully reduced tumor progression associated with cell cycle arrest. Recently, nanoparticle liposome-based complexes targeting the transferrin receptor single chain antibody fragment have been used to specifically target tumors in gene therapy. By combining these concepts, we hypothesize that CaSm functions as a "master switch" to destabilize multiple gene transcripts, contributing to the malignant phenotype observed in pancreatic cancer which will be effectively targeted by CaSm siRNA delivered by a novel transferrin-targeted nanovector system. This novel approach should overcome significant obstacles facing gene therapy such as low transfection efficiency, poor tissue penetrance, and non-specific delivery of drug to target. This K08 will enable the applicant to define the critical molecular pathways involved in CaSm-mediated oncogenesis in pancreatic cancer and to secure a future career as an independent clinician-scientist performing successful translational research. This research program will provide: (1) strong mentoring relationships;(2) exposure to national and international audiences in our field of study;(3) establishment of a productive research environment;and (4) assistance for achieving independent funding. A Career Development Committee has been created to assess progress on a quarterly basis. With the applicant's basic science foundation established through prior research training along with completion of a Masters of Science in Clinical Research program (May 2009), the applicant is prepared to embark on the next phase towards an independent research program that will include training in technical aspects of gene cloning and suppression, design and analysis of bioinformatic approaches including microarray analysis, and design and analysis of therapeutic in vivo models. These research efforts will primarily be supported through weekly meetings with co-mentors to address conceptual and technical issues faced within the proposed research, and generation and preparation of manuscripts and grants. Finally, this project will establish the role of CaSm gene therapy in pancreatic cancer and serve as the foundation of future clinical trials in patients with pancreatic cancer. Such evaluation of the novel transferrin-targeted nanovector as a tumor specific siRNA delivery mechanism may enhance gene therapy strategies designed for pancreatic cancer and serve as a model for other malignancies. PUBLIC HEALTH RELEVANCE: Pancreatic cancer is devastating and remains the 4 leading cause of cancer related deaths in the US. Gene therapy is likely the next step for new treatment approaches in pancreatic cancer and our research group has identified a promising new molecular target, CaSm that may improve current treatment. Similarly, addressing the major problem of poor gene therapy delivery may lead to more successful treatments for pancreatic cancer which are badly needed and serve as a model for other cancers.